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The Virtuoso TM system provides automated digital slide creation, management, analysis, and viewing. It is intended for in vitro diagnostic use as an aid to the pathologist in the display, detection, counting, review and classification of tissues and cells of clinical interest based on particular morphology, color, intensity, size, pattern and shape.

The Virtuoso™ System for IHC PR (1E2) using the VENTANA iScan HT is for the digital read application. This particular Virtuoso system is intended for use as an aid to the pathologist in the qualitative detection of progesterone receptor (PR) protein in formalin-fixed, paraffin-embedded normal and neoplastic tissue. This device is an accessory to Ventana Medical Systems, Inc. CONFIRM anti-Progesterone Receptor (PR) (1E2) Rabbit Monoclonal Primary Antibody assay. The CONFIRM™ anti-Progesterone Receptor (PR) (1E2) Rabbit Monoclonal Primary Antibody assay is indicated for use as an aid in the assessment of breast cancer patients for whom endocrine treatment is being considered (but is not the sole basis for treatment).

Note: The IHC PR (1E2) Digital Read application is an adjunctive computer-assisted methodology for the qualified pathologist in the acquisition and interpretation of images from microscope glass slides of breast cancer specimens stained for the presence of PR protein. The accuracy of the test results depends on the quality of the immunohistochemical staining. It is the responsibility of a qualified pathologist to employ appropriate morphological studies and controls as specified in the instructions for the CONFIRM™ anti-Progesterone Receptor (PR) (1E2) Rabbit Monoclonal Primary Antibody used to assure the validity of the Virtuoso System for IHC PR Digital Read scores. The actual correlation of CONFIRM™ anti-PR antibody to clinical outcome has not been established. This device is intended for IHC slides stained on the BenchMark ULTRA stainers. For prescription use only.

The Virtuoso™ System is an instrument-plus-software system designed to assist the qualified pathologist in the consistent assessment of protein expression in immunohistochemically stained histologic sections from formalin-fixed, paraffinembedded normal and neoplastic tissues. The system consists of a slide scanner, computer, monitor, keyboard, and mouse for specific immunohistochemical markers, and software with a Windows web browser-based user interface. Virtuoso is a web-based, end-to-end, digital pathology software solution that allows pathology laboratories to acquire, manage, view, analyze, share, and report digital images of pathology specimens. Using the Virtuoso software, the pathologist can view digital images, add annotations and generate reports.

Hardware: The iScan HT scanning device captures digital images of formalinfixed, paraffin-embedded tissues that are suitable for storage and viewing. The device includes a digital slide scanner, a carousel for loading glass slides, computer, scanner software, keyboard, mouse and monitor.

Software: The Virtuoso software is designed to complement the routine workflow of a qualified pathologist in the review of immunohistochemically stained histologic slides. The software makes no independent interpretations of the data and requires competent human intervention for all steps in the process.

Acceptance Criteria and Device Performance for Virtuoso™ System for IHC PR (1E2) using the VENTANA iScan HT

This response summarizes the acceptance criteria and study findings for the Virtuoso™ System for IHC PR (1E2) using the VENTANA iScan HT, based on the provided FDA 510(k) summary (K142965).

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are implicitly derived from the reported agreement rates. For the purpose of this table, we will highlight the reported agreement rates as the measure of meeting the acceptance of substantial equivalence.

Note: The document states that the test system was shown to be "as safe and effective (therefore substantially equivalent) as the predicate devices". The provided agreement rates are the key metrics demonstrating this substantial equivalence. Specific predefined numerical acceptance criteria are not explicitly stated as distinct thresholds in the provided text but are implicitly met by achieving high concordance with manual methods and good reproducibility, consistent with existing legally marketed devices.

2. Sample Size Used for the Test Set and Data Provenance

• Sample Size for Method Comparison Test Set:
  • Site 1: 159 cases
  • Site 2: 162 cases
  • Site 3: 156 cases
  • Overall: 477 cases (sum of evaluable cases from the three sites)
• Sample Size for Reproducibility Test Set: 39 cases (for intra-pathologist reproducibility)
• Sample Size for Scanner Precision Test Set: 40 cases
• Data Provenance: The document does not explicitly state the country of origin. However, the study involved three different "sites", implying a multi-center study possibly within the US, but this is not explicitly confirmed. The study appears to be retrospective in nature, using existing formalin-fixed, paraffin-embedded tissue blocks that were then stained and digitally scanned.

3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications

• Number of Experts: 3 pathologists (referred to as "Readers" or "Investigators"). The method comparison study involved each of these 3 pathologists providing both manual and digital reads. The reproducibility studies also involved these 3 pathologists.
• Qualifications of Experts: The document refers to them as "qualified pathologists" or "investigators." Specific details regarding their years of experience or sub-specialty (e.g., radiologist, breast pathologist) are not provided.

4. Adjudication Method for the Test Set

• Method Comparison: The ground truth for the device's performance was established using the manual read (MR) by the same pathologist as the reference for the digital read (DR) evaluation. Each pathologist's DR results were compared to their own MR results. There is no explicit mention of an independent adjudication committee or consensus among multiple experts for the ground truth itself.
• Reproducibility: For intra-pathologist reproducibility, the comparison was between the same pathologist across three different reading sessions. For inter-pathologist reproducibility, the comparison was between pairs of pathologists.
• Scanner Precision: The comparison was between clinical scoring categories agreed upon at different sites/days for the same FOVs.
• It appears no formal "N+1" or similar adjudication method was employed to establish a single, definitive ground truth independent of the readers whose digital reads were being assessed. Instead, the agreement between the digital read and a human's manual read served as the primary performance indicator, and reproducibility between humans (both manual and digital) was also evaluated.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done, and Effect Size

• Yes, a form of MRMC study was implicitly done. The method comparison study involved 3 pathologists (multi-reader) evaluating multiple cases (multi-case), where their digital reads were compared to their manual reads. The reproducibility studies also involved multiple readers and multiple cases.
• Effect Size (Human Reader Improvement with AI vs. without AI): The document does not report an effect size for human readers improving with AI assistance. The study design is primarily focused on demonstrating the substantial equivalence of the digital read system to the manual read, rather than measuring the improvement in human performance when assisted by the AI. The Virtuoso™ System is described as an "aid to the pathologist" and an "adjunctive computer-assisted methodology," but the study evaluates its standalone performance against manual reading, and its reproducibility, not its comparative effectiveness in improving reader accuracy or efficiency.

6. If a Standalone (Algorithm Only Without Human-in-the-Loop Performance) Was Done

• No, a standalone (algorithm only) performance study was not done or reported. The device is described as an "aid to the pathologist" and the software explicitly "makes no independent interpretations of the data and requires competent human intervention for all steps in the process."
• The Digital Read (DR) method involves the pathologist reviewing the digital images. The performance metrics (OPA, PPA, NPA) are based on the pathologist's interpretation using the digital system, not an automated algorithm's output directly.

7. The Type of Ground Truth Used

• The primary ground truth used for the method comparison study was the expert's own manual microscopic assessment of the formalin-fixed, paraffin-embedded tissue slides, using a traditional microscope. This acts as the "reference manual method."
• For the reproducibility and precision studies, the ground truth for comparison was the clinical score assigned by pathologists (either their own previous scores for intra-reader, or other pathologists' scores for inter-reader/inter-scanner).
• The ground truth categories were defined as:
  • Negative: PR score of 0 to 0.99% positive staining
  • Positive: PR score of ≥1% positive staining
  • For scanner precision: 0 – 0.99%, 1–10%, and ≥ 10% positive staining.
• There is no mention of pathology or outcomes data being used as an independent, external ground truth beyond expert consensus.

8. The Sample Size for the Training Set

• The document does not provide information on the sample size used for the training set for the Virtuoso™ System's software. The study focuses on the clinical validation of the device, implying that the algorithm development (training) phase was completed prior to these validation studies.

9. How the Ground Truth for the Training Set Was Established

• The document does not provide information on how the ground truth for the training set was established. This information is typically part of the device development process and is not always included in the 510(k) summary for validation studies.

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The Omnyx Manual Read of the Digital HER2 Application on the Omnyx IDP System is intended for in vitro diagnostic use as an aid to pathology professionals for creating, storing, annotating, measuring, and viewing digital Whole Slide Images (WSI) from formalin-fixed, paraffin-embedded (FFPE) tissue sections stained with the Dako HercepTest™.

The Omnyx Manual Read of the Digital HER2 Application on the Omnyx IDP System is intended for use as an aid to the pathologist in the detection and semi-quantitative measurement of HER2/neu (c-erbB-2) in digital images of FFPE breast cancer tissue immunohistochemically stained with the Dako HercepTest™ and viewed on a computer monitor.

The Dako HercepTest™ is indicated for use as an aid in the assessment of breast cancer patients for whom HERCEPTIN® (Trastuzumab) treatment is being considered.

The Omnyx Manual Read of the Digital HER2 Application on the Omnyx IDP System is intended to aid pathology professionals in creating, storing, annotating, measuring, and viewing digital Whole Slide Images (WSI) from formalin-fixed, paraffin-embedded (FFPE) tissue sections stained with the Dako HercepTest™.

The system is composed of the following components:

• VL4 Scanner: A hardware device that captures and compresses bright field images of tissue samples.
• Data and Workflow Infrastructure: A set of networked applications which enables case data entry, acquisition, indexing, storage and acceptance of digital images, workflow management, and retrieval of case and image data.
• Histology Workstation: The application which permits the histologist to review or enter case data and check quality of scanned images.
• Pathology Workstation: The application which allows the pathologist to retrieve case data and review and annotate slide images.

Hardware:
The Omnyx™ VL4 scanner is an automated imaging system that can be loaded with up to 4 slides at a time. The VL4 Scanner outputs its images and metadata to the Omnyx Digital Archive, which receives and stores the images and data.

Software:
The Omnyx software is composed of 1) the VL4 scanner software which performs tissue identification, scan planning, focusing, image acquisition, stitching and compression of digital slide images and sends them to the Digital Archive and 2) the DPS software that manages the Histologist and Pathologist workstation functions, image viewer, workflow service, database, interface engine, APLIS service, digital archive, image store and the administrator client application.

Here's a breakdown of the acceptance criteria and the study that proves the Omnyx Manual Read of the Digital HER2 Application meets these criteria, based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are implicitly defined by the clinical comparison and precision/reproducibility studies, aiming to demonstrate non-inferiority to manual microscopy and reliable performance. The studies evaluate agreement between different modalities (manual vs. digital) and within identical modalities but different readers/days/scanners.

2. Sample Size Used for the Test Set and Data Provenance

• Clinical Comparison (MM vs. M-WSI):
  • Sample Size: 200 breast cancer cases (samples stained with Dako HercepTest™ and controls).
  • Data Provenance: Not explicitly stated, but the study was conducted comparing reads from conventional manual microscopes and the Omnyx IDP system, suggesting it was based on existing clinical samples. It is not specified if the data was retrospective or prospective, or the country of origin.
• Precision & Reproducibility (Intra-Reader/Inter-Day):
  • Sample Size: 40 HercepTest™ stained slides.
  • Data Provenance: Not explicitly stated (retrospective/prospective, country of origin).
• Precision & Reproducibility (Inter-Scanner/Intra-Reader):
  • Sample Size: 80 regions of interest (ROIs) extracted from 40 HercepTest™ slides, with an even distribution of score categories.
  • Data Provenance: The three scanners were located in "three different laboratory locations within GE Healthcare and operated by three independent operators." This indicates multi-site internal data.

3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts

• Clinical Comparison (MM vs. M-WSI):
  • Number of Experts: Four (4) pathologists.
  • Qualifications: Not explicitly stated beyond "pathologists."
  • Ground Truth: For the inter-reader/intra-modality analysis, the comparisons are between pathologists, so no single "ground truth" is established by an expert panel; rather, concordance between experts is assessed. For the inter-modality/intra-reader comparison, the glass slide read by each pathologist serves as their imperfect reference for their digital read.
• Precision & Reproducibility (Intra-Reader/Inter-Day):
  • Number of Experts: Three (3) pathologists.
  • Qualifications: Not explicitly stated beyond "pathologist."
  • Ground Truth: Not applicable in this context; the study assesses a single pathologist's reproducibility over time, not against an external "ground truth."
• Precision & Reproducibility (Inter-Scanner/Intra-Reader):
  • Number of Experts: A single pathologist.
  • Qualifications: Not explicitly stated beyond "a single pathologist."
  • Ground Truth: The manual scores by this single pathologist served as the reference for comparing ROIs from different scanners.

4. Adjudication Method for the Test Set

• Clinical Comparison (MM vs. M-WSI): No formal adjudication method is mentioned for establishing a single "ground truth" across readers. The study focuses on pairwise agreement between pathologists and agreement of an individual pathologist across modalities. For the binary agreement calculations, "neither pathologist can be considered a reference in each pairwise reader comparison," so Average Negative Agreement (ANA) and Average Positive Agreement (APA) are used instead of traditional sensitivity/specificity against a single ground truth.
• Precision & Reproducibility (Intra-Reader/Inter-Day): Not applicable; this study assessed intra-reader variability over time.
• Precision & Reproducibility (Inter-Scanner/Intra-Reader): A single pathologist established the scores for the ROIs, effectively acting as the adjudicator/reference for scanner comparisons.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance

• No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not performed in the sense of AI assistance improving human reader performance.
• The study design focused on demonstrating that the digital platform (Omnyx IDP System with manual reading) is substantially equivalent to manual microscopy. It evaluates the concordance between pathologists using traditional manual methods and pathologists using the digital system.
• The device described is the "Omnyx Manual Read of the Digital HER2 Application," implying no AI algorithm for automated scoring or triage that would "assist" the human reader. The pathologist still performs the interpretation manually, but on digital images rather than glass slides.

6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) was done

• No. The device is explicitly for "Manual Read of the Digital HER2 Application." Its intended use states it is "an aid to pathology professionals" and "an aid to the pathologist in the detection and semi-quantitative measurement of HER2/neu...viewed on a computer monitor." This indicates it's a tool for manual interpretation of digital images, not an automated algorithm for standalone performance.

7. The Type of Ground Truth Used

• Clinical Comparison (MM vs. M-WSI):
  • For inter-reader/intra-modality comparisons, concordance between pathologists serves as the metric, not an external "ground truth."
  • For inter-modality/intra-reader comparisons ("MM vs. M-WSI"), the glass slide read by each pathologist was used as their respective imperfect reference. This is explicitly stated, indicating that it's considered an imperfect reference rather than a definitive, independently verified ground truth.
• Precision & Reproducibility (Inter-Scanner/Intra-Reader): The 80 ROIs were "manually scored by a single pathologist based on the Dako HercepTest™ scoring guidelines." This single pathologist's score serves as the ground truth for evaluating inter-scanner agreement.

8. The Sample Size for the Training Set

• The document does not explicitly mention a "training set" or "validation set" in the context of an AI algorithm learning to interpret images.
• Since this device is a "Manual Read" application that facilitates human interpretation of digital slides, rather than an AI algorithm for automated diagnosis, the concept of a training set as typically understood for AI models is not applicable or discussed. The studies describe performance evaluation sets for human readers.

9. How the Ground Truth for the Training Set was Established

• As mentioned above, a "training set" for an AI model is not discussed in this document, as the device is for manual interpretation of digital slides. Therefore, the establishment of ground truth for such a set is not applicable here.

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The Philips HER2/neu IHC Digital Manual Read is intended for in vitro diagnostic use as an aid to the pathologist in the display, detection, counting and classification of tissues and cells of clinical interest based on particular color, intensity, size, pattern and shape. The Philips HER2/neu IHC Digital Manual Read is based on the Philips Digital Pathology Solution platform, which is an automated digital slide creation, management, viewing and analysis system.

The Philips HER2/neu IHC Digital Manual Read is intended for use as an accessory to the Dako HercepTest™ to aid in the detection and semi-quantitative measurement of HER2/neu (c-erbB-2) in formalin-fixed, paraffin-embedded neoplastic tissue immunohistochemically stained for HER-2 receptors on a computer monitor. When used with the Dako HercepTest™, it is indicated for use as an aid in the assessment of breast cancer patients from whom HERCEPTIN® (Trastuzumab), PERJETA® (Pertuzumab) or KADCYLA® (Ado-Trastuzumab Emtansine) treatment is being considered. Note: The actual correlation of the Dako HercepTest™ to Herceptin®, Perjeta®, or Kadcyla®, clinical outcome has not been established.

Note: The Philips HER2/neu IHC Digital Manual Read is for evaluation of digital images of immunohistochemically stained slides that would otherwise be appropriate for manual visualization by conventional microscopy. It is the responsibility of a qualified pathologist to employ appropriate morphological studies and controls as specified in the instructions for Dako HercepTest™ to assure the validity of the scores obtained using Philips HER2/neu IHC Digital Manual Read.

The Philips HER2/neu IHC Digital Manual Read is a digital manual read application and an adjunct to primary diagnosis. The application utilizes the Philips Digital Pathology Solution (DPS) platform that includes a Philips Ultra Fast Scanner (UFS) and Philips Image Management System (IMS).

The Philips Digital Pathology Solution is an automated digital slide creation, management, sharing, viewing and analysis system. It is intended for in vitro diagnostic use as an aid to the pathologist in the display, detection, counting and classification of tissues and cells of clinical interest based on particular color, intensity, size, pattern and shape.

The Philips UFS system digitizes slides at high resolution and generates the whole slide images (WSI). The Philips UFS also takes snapshot images of the entire glass slide as well as the glass slide label and decodes the barcode. Based on the macro image of the scanner determines which region on the slide will be scanned. All images, WSI and snapshot images together with information about the decoded barcode are sent to the Philips Image Management System (Philips IMS).

The Phillips IMS comes supplied with the Barco MDCC 2121 monitor and runs on commercially available server and workstation IT hardware which are specified by Philips and purchased by the customer. The server stores and manages the digital slide images and digital slide metadata. The server supports interoperability with other information systems such as the laboratory information systems (LIS) via a HL7 interface. The IMS Web Viewer software provides the User Interface for the pathologist to view and read the digital slides.

Here's a breakdown of the acceptance criteria and the study that proves the device meets them, based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly state formal acceptance criteria with specific threshold values for the performance metrics. Instead, it describes clinical studies aiming to demonstrate substantial equivalence to manual optical reading. The conclusion states that "All of the method comparison and precision clinical studies components met the expected acceptance criteria." This implies that the observed agreements were considered sufficient, even if a numerical threshold wasn't articulated in the summary.

Inferred "Acceptance" (demonstrated performance) and Reported Device Performance:

2. Sample Size for Test Set and Data Provenance

• Sample Size (Method Comparison Study): Two hundred (200) formalin-fixed, paraffin-embedded breast tissue specimens. Each specimen was scored by 3 pathologists using two different methods, resulting in 6 study reads per specimen. However, the 4x4 tables show totals around 184-196, indicating some slides might have been excluded due to quality issues.
• Sample Size (Intra-Pathologist Precision Study): A target set of 8 HercepTest™ slides, evaluated 5 times for each method (Manual Digital and Manual Optical). To reduce bias, these 8 slides were mixed with an additional set of 12 "wild card" slides for each reading session (total of 20 slides per session).
• Sample Size (Inter-Pathologist Precision Study): This study utilized the data collected from all sites in the method comparison study (i.e., all 200 specimens scored by 3 pathologists).
• Sample Size (Instrument Precision Studies): 40 HercepTest™ stained tissue slides (core slides). These were augmented with 32 "wild card" slides for each reading session.
• Data Provenance: The specimens were obtained from a tissue bank of de-identified human specimens. The country of origin is not specified, but the applicant is based in the Netherlands. The study simulates the use environment (three pathologists from two sites participated). The nature of the historical tissue bank makes it retrospective.

3. Number of Experts and Qualifications for Ground Truth for the Test Set

The concept of a single "ground truth" for the test set, as might be established by pathology or outcomes data, is not directly applicable here. This study primarily compares two methods of interpretation (manual optical vs. manual digital) by human pathologists.

• Method Comparison Study:

  • Number of "Experts": Three (3) pathologists.
  • Qualifications: "The pathologists in the study were trained in the use of the investigational device according to the labeling." No further specific qualifications like years of experience or board certification are detailed for these three.
  • "Ground Truth": No external "ground truth" was established a priori. The study aims to demonstrate concordance between the two reading methods by the same pathologists. The slides were prescreened by a pathologist (not necessarily one of the study pathologists) to evaluate staining quality and provide an initial score, which was used for selection to ensure a balanced distribution of scores, but this initial score was not treated as the definitive ground truth against which study observations were compared.

• Intra-Pathologist Precision Study:

  • Number of "Experts": One (1) pathologist.
  • Qualifications: Not explicitly stated beyond "a pathologist."
  • "Ground Truth": The "median values of the scores provided by the pathologist over 5 runs" were used as the reference against which outlying scores were identified for agreement calculation.

• Inter-Pathologist Precision Study:

  • Number of "Experts": Three (3) pathologists.
  • Qualifications: Not explicitly stated beyond "pathologists."
  • "Ground Truth": No external "ground truth." This study evaluated agreement among the pathologists' readings.

• Instrument Precision Studies:

  • Number of "Experts": Two (2) board-certified pathologists. One for Inter-S and one for IDIS.
  • Qualifications: "Two board-certified pathologists."
  • "Ground Truth": The specimens were "pre-scored... by a pathologist not involved in the study" to ensure equal distribution of scores, but this pre-score was not used as definitive ground truth for the analyses presented. The study assessed the consistency of interpretation of images generated by different scans/days by the assigned study pathologist.

4. Adjudication Method for the Test Set

For the method comparison and precision studies:

• No explicit adjudication method (like 2+1 or 3+1) was used to establish a definitive ground truth by consensus among multiple experts.
• Instead, the studies focused on concordance between the manual optical reading and the manual digital reading by the same pathologist, and then on agreement among different pathologists' readings for inter-pathologist precision.

5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study

• Yes, a form of MRMC study was done in the "Method Comparison (Manual Digital vs. Manual Optical)" section. It compared the performance of human readers (pathologists) using a traditional optical microscope versus using the Philips HER2/neu IHC Digital Manual Read system.
• Effect Size of AI vs. Without AI Assistance:
  The device is described as "No image analysis algorithms are applied to these systems (i.e. digital manual read only)." This means the device itself does not include any AI assistance for interpretation; it is a digital display system for manual reading by a human. Therefore, there is no reported effect size of how much human readers improve with AI vs. without AI assistance because the "AI" component is absent from the interpretation process. The study demonstrates the equivalence of manual digital reading to manual optical reading.

6. Standalone (Algorithm Only) Performance

• No standalone (algorithm only) performance study was done because the device is explicitly a "Digital Manual Read" application and "No image analysis algorithms are applied to these systems." The device functions as a display and management system for images that are still manually interpreted by a pathologist.

7. Type of Ground Truth Used

As elaborated in point 3, the studies did not use a single, external "ground truth" (such as unanimous expert consensus, pathology, or outcomes data) against which the device's performance was measured in an absolute sense.

• Method Comparison: The "ground truth" was effectively the pathologist's own reading using the conventional optical microscope, against which their reading using the digital system was compared for agreement.
• Precision Studies: The "ground truth" was either the pathologist's median score (for intra-pathologist) or the agreement among pathologists (for inter-pathologist).
• For the instrument precision studies, the comparison was based on consistency of scores by a single pathologist across different scans/days/instruments.

8. Sample Size for the Training Set

• The document describes a "Digital Manual Read" device, which means it is a display and management system for pathologists to manually interpret whole slide images. It explicitly states, "No image analysis algorithms are applied to these systems."
• Therefore, there is no AI algorithm being "trained," and consequently, there is no "training set" of data for an AI model.

9. How Ground Truth for Training Set Was Established

• As there is no AI algorithm that requires training, there is no training set and no ground truth established for a training set.

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The VS800 system is an automated digital slide creation, management, and viewing system. It is intended for in vitro diagnostic use as an aid to the pathologist in the display, detection, counting and classification of tissues and cells of clinical interest based on particular color, intensity, size, pattern and shape.

The VS800HER2 Manual Read (MR) of digital slide application is intended for use as an aid to the pathologist in the detection and semi-quantitative measurement of HER2 by manual examination of the digital slide of formalin-fixed, paraffin-embedded and neoplastic tissue IHC stained for HER2 receptors on a computer monitor. HER2 results are indicated for use as an aid in the management, prognosis and prediction of therapy outcomes of breast cancer.

The VS800HER2 MR of digital slide application is intended for use as an accessory to the DakoHercepTest to aid the pathologist in the detection and semi-quantitative measurement of HER2 by manual examination of the digital slide of formalin-fixed, paraffin-embedded and neoplastic tissue immunohistochemically stained for HER2 receptors on a computer monitor. When used with the Dako Hercep Test, it is indicated for use as an aid in the assessment of breast cancer patients for whom HERCEPTIN® (Trastuzumab) treatment is being considered.

Note: The actual correlation of the Dako Hercep Test to the Herceptin® clinical outcome has not been established.

The VS800 System is an automated digital slide creation, management and viewing system. The VS800 System components consist of an automated digital microscope slide scanner (VS800-SS) which include a computer, keyboard and mouse, operating monitor (VS800-MTR) and VS Viewer software (VS2-ASW-IDB). The system capabilities include digitizing microscope slides at high resolution, storing and managing the resulting digital slide images, retrieving and displaying digital slides, including support for remote access over wide-area networks, providing facilities for annotating digital slides and editing metadata associated with digital slides, and facilities for image analysis of digital slides. The remote digital slide viewing capabilities of the system support reading digital slides on a computer monitor, enabling Pathologists to make clinically relevant decisions analogous to those they make using a conventional microscope. Specifically, the system supports the pathologist in the detection of HER2/neu by manual examination of the digital slide of formalin-fixed, paraffin-embedded normal and neoplastic tissue immunohistochemically stained for HER2 receptors on a computer monitor.

The VS800-SS (an automated digital microscope slide scanner) creates high resolution, color digital slide images of entire glass slides in a matter of minutes. High numeric aperture 20x objectives, specially designed for VS800-SS optical system and real time contrast auto focus system (AF) are used to produce high-quality images. VS800-SS employs a 2D CCD imager for fine image acquisition which is same technologies used in conventional microscope imaging system. VS800-SS captured image is as same as conventional microscope image.

The VS-ASW-IDB (VS Viewer software) is a full-featured digital pathology information management system. The software runs on a server computer, which stores digital slide images on disk storage such as a RAID array, and which hosts an SQL database that contains digital slide metadata. The VS-ASW-IDB includes a web application and services which encapsulate database and digital slide image access for other computers. The VS-ASW-IDB also includes support for locally or remotely connected Image Server, which run digital slide viewing software provided as part of VS-ASW-IDB.

The laboratory technician or operator of VS800-SS loads glass microscope slides into a specially designed slide carrier with a capacity up to 100 slides per carrier (300 total). The scanning process begins when the operator starts the VS800-SS scanner and finishes when the scanner has completed scanning of all loaded slides. As each glass slide is processed, the system automatically stores stitched images as a single digital slide image, which represents a histological reconstruction of the entire tissue section. When the slide scanning finished, then operator of scanner will confirms the image quality and records to the database. When the images are recorded, pathologists or authorized parsons can observe these images to access the VS-ASW-IDB.

Here's a summary of the acceptance criteria and study details for the Olympus VS800HER2 MR Application, based on the provided 510(k) summary:

Acceptance Criteria and Device Performance

Note: The study describes percentages of agreement without predefined acceptance thresholds for substantial equivalence in the document. The statistical analysis is presented as Percent Agreement (PA) with a 95% Confidence Interval (CI) between manual microscopy reads and manual digital reads, and for precision studies.

Study Details for the Olympus VS800HER2 MR Application

1. Sample Size Used for the Test Set and Data Provenance:

   • Sample Size: 100 slides per clinical site, so a total of 200 slides were used for the comparison study (100 slides at Site 1, 100 slides at Site 2).
   • For the precision study, a subset of 30 slides from the comparison study was used.
   • Data Provenance: Retrospective. The slides were "selected from archive." The country of origin is not explicitly stated, but the study was conducted at "two clinical sites," implying local (likely within the US, given FDA submission context) data.

2. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts:

   • Number of Experts: Six pathologists in total for the comparison study (three at each of two clinical sites). One pathologist for the precision study (who repeated reads).
   • Qualifications of Experts: Described as "Pathologists." Specific years of experience or sub-specialty certifications are not provided in the summary.

3. Adjudication Method for the Test Set:

   • Adjudication Method: None for establishing a single "ground truth." The study compared each pathologist's "manual digital reads" against their own "manual microscopy reads." This is a paired comparison, where the conventional microscopy read by the same pathologist is considered the reference for that pathologist's digital read. The summary doesn't describe an external or consensus ground truth for the comparison study itself; rather, it assesses agreement between two reading methods by the same individual.
   • For the precision study, there was also no external adjudication; it assessed agreement of repeated reads by a single pathologist.

4. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance:

   • This was a Multi-Reader Multi-Case (MRMC) comparative effectiveness study of digital pathology reads vs. conventional microscopy reads, but without AI assistance. The VS800HER2 MR Application is a "Manual Read" application, meaning the pathologist manually interprets the digital image.
   • Therefore, there is no AI component, and no effect size regarding human readers improving with AI assistance is reported or applicable to this specific application. The study focuses on the agreement between conventional microscopy and manual reading of digital slides.

5. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done:

   • No standalone algorithm-only performance study was done. The device (VS800HER2 MR Application) is explicitly described as for "Manual Read (MR) of digital slide application," intended "as an aid to the pathologist in the detection and semi-quantitative measurement of HER2 by manual examination of the digital slide." It is a display and management system for pathologists to manually review digital slides, not an automated AI-driven diagnostic algorithm.

6. The type of ground truth used (expert consensus, pathology, outcomes data, etc.):

   • For the comparison study: The "ground truth" or reference standard for each pathologist's digital read was their own prior manual microscopy read of the physical glass slide. This is a paired comparison, where the same pathologist acts as their own control.
   • For the precision study: The reference was the pathologist's own repeated manual digital reads from the same or different instruments.

7. The sample size for the training set:

   • The 510(k) summary does not mention a training set for an algorithm, as the VS800HER2 MR Application is a manual read application. The study described is entirely a clinical validation/test set.

8. How the ground truth for the training set was established:

   • Not applicable, as there is no mention of a training set or an algorithm being developed (which would typically require a training set with established ground truth). The device acts as a digital visualization and management system for manual pathologist interpretation.

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The ScanScope® System is an automated digital slide creation, management, viewing and analysis system. It is intended for in vitro diagnostic use as an aid to the pathologist in the display, detection, counting and classification of tissues and cells of clinical interest based on particular color, intensity, size, pattern and shape.

The ScanScope® system is intended for use as an aid to the pathologist in the detection and quantitative measurement of PR (Progesterone Receptor) by manual examination of the digital slide of formalin-fixed, paraffin-embedded normal and neoplastic tissue immunohistochemically stained for PR on a computer monitor.

It is indicated for use as an aid in the management, prognosis, and prediction of therapy outcomes of breast cancer.

The system comprises a ScanScope® XT digital slide scanner instrument and a computer system executing Spectrum " software. The system capabilitics include digitizing microscope slides at diagnostic resolution, storing and managing the resulting digital slide images, retrieving and displaying digital slides, including support for remote access over wide-area networks, providing facilities for annotating digital slides and entering and editing metadata associated with digital slides, and facilities for image analysis of digital slides, including the ability to quantify characteristics useful to Pathologists, such as measuring and scoring immunohistochemical stains applied to histology specimens, such as Dako PR, which reveal the presence of PR (Progesterone Receptor) protein expression, which may be used to determine patient treatment for breast cancer.

The provided document, K080254, describes the Aperio ScanScope® XT System, intended for in vitro diagnostic use as an aid to pathologists in the display, detection, counting, and classification of tissues and cells of clinical interest. Specifically, the document focuses on its use for the detection and quantitative measurement of Progesterone Receptor (PR) by manual examination of digital slides.

Here's an analysis based on the requested information:

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are implicitly based on the agreement between manual microscopy and manual reading of digital slides, and the reproducibility of the digital slide system. The document does not explicitly state pre-defined numerical acceptance criteria (e.g., "agreement must be >X%"). Instead, it reports the range of observed agreements and precision metrics.

2. Sample Size Used for the Test Set and Data Provenance

• Test Set Sample Size: 180 formalin-fixed, paraffin-embedded breast tissue specimens.
  • Clinical Site 1: 80 slides.
  • Clinical Site 2: 100 slides.
• Data Provenance: The study was conducted at two Clinical Laboratory Improvement Amendments (CLIA) qualified clinical sites. The specimens were immunohistochemically stained at these clinical sites using Dako IVD FDA cleared reagents. Glass slides were prepared in the sites' clinical laboratories.
  • Clinical Site 1: Specimens selected based on existing clinical scores to provide an equal distribution of PR slides across different percentage positive nuclei ranges (0%, 1-9%, 10-49%, 50-100%).
  • Clinical Site 2: Routine specimens taken from clinical operations, representing a typical clinical setting.
• Retrospective/Prospective: Not explicitly stated as strictly retrospective or prospective. The specimens were "from both clinical sites" and for Site 1, "selected based on their clinical scores on file," suggesting a retrospective selection of cases. For Site 2, "routine specimens taken from their clinical operation" could imply concurrent collection or a recent retrospective selection. The reading of these slides by pathologists for the study itself was a prospective activity within the study design.

3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts

• Number of Experts: Three different board-certified pathologists at each of the two clinical sites were used. This totals 6 pathologists for the initial manual reads (3 at site 1, 3 at site 2). Later, for the digital reads, the "same three Pathologists at each clinical site" performed the digital read. It's unclear if the same 6 pathologists or 3 total pathologists across both sites participated in all stages. However, for ground truth generation, it was 3 pathologists per site.
• Qualifications of Experts: "Board-certified staff pathologists."

4. Adjudication Method for the Test Set

The "ground truth" for the comparison study was established by the consensus or average of the three pathologists' manual microscopy reads. The statistical analyses were presented for each of the scores (percentage of positive nuclei and intensity scores) and "comparatively between the two methods for the clinical sites with their different three pathologists." This implies a form of expert consensus, where the average/distribution of their reads served as the reference for comparison, rather than a formal adjudication to a single "correct" answer by an independent panel.

5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study

• Was an MRMC study done? Yes, a comparative study was conducted where three pathologists at each of two clinical sites read 180 cases by traditional manual microscopy and then later (after a wash-out period and randomization) read the digital slides of the same cases on a computer monitor. This fits the description of a multi-reader, multi-case comparison study.
• Effect size of human readers improve with AI vs without AI assistance: This study does not describe AI assistance for human readers. The ScanScope® XT System is described as a digital slide creation, management, viewing, and analysis system intended as an aid to the pathologist by manual examination of digital slides. The analytical performance section mentions an "image analysis algorithm," but this algorithm was used for precision/reproducibility studies of the system itself, not to assist pathologists in their interpretation of diagnostic cases. The clinical comparison study directly compares manual microscopy performance to human pathologists reading digital slides visually. Therefore, an effect size of human readers with AI vs without AI assistance is not reported because the clinical study did not involve AI assistance for the pathologists.

6. Standalone (Algorithm Only Without Human-in-the-Loop Performance) Study

• Was a standalone study done? No, a standalone study demonstrating the algorithm's diagnostic performance without human-in-the-loop was not performed or reported for its intended diagnostic use.
  • An "image analysis algorithm" was used in the analytical performance (precision/reproducibility) section to quantify cell features and scoring schemes objectively. This algorithm reported percentage of positive nuclei and intensity scores for system assessment, not for diagnostic claims for the algorithm itself. It was used to understand scanning variability, not to replace or assist a pathologist's diagnosis.

7. Type of Ground Truth Used

The ground truth for the comparison study (clinical performance) was established by expert consensus based on the average/distribution of manual microscopy readings from three board-certified pathologists for each slide. The Dako IVD FDA cleared Monoclonal Mouse Anti-Human Progesterone Receptor (Clone PgR 636) (K020023) was used for immunohistochemical staining, providing a standardized basis for the pathologists' assessment.

8. Sample Size for the Training Set

The document does not mention a training set for the ScanScope® XT System itself, as it is a digital slide scanner and management system, with the focus of the clinical study being on the equivalence of manual pathologist interpretation of digital slides compared to glass slides. The "image analysis algorithm" used in the analytical performance section is not presented as a component needing a separate training set for diagnostic purposes described here.

9. How the Ground Truth for the Training Set Was Established

As no training set is described for a diagnostic algorithm, the method for establishing its ground truth is not applicable in this context. The clinical study focuses on establishing the equivalence of the digital viewing method to conventional microscopy, with the human pathologist remaining the primary interpreter.

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The ScanScope® System is an automated digital slide creation, management, viewing and analysis system. It is intended for in vitro diagnostic use as an aid to the pathologist in the display, detection, counting and classification of tissues and cells of clinical interest based on particular color, intensity, size, pattern and shape.

The IHC HER2 Manual Read of Digital Slides application is intended for use as an aid to the pathologist in the detection and semi-quantitative measurement of HER-2/neu (cerbB-2) by manual examination of the digital slide of formalin-fixed, paraffin-embedded normal and neoplastic tissue immunohistochemically stained for HER-2 receptors on a computer monitor. HER2 results are indicated for use as an aid in the management, prognosis and prediction of therapy outcomes of breast cancer.

The IHC HER2 Manual Read of Digital Slides application is intended for use as an accessory to the Dako HercepTest™ to aid the pathologist in the detection and semi-quantitative measurement of HER-2/neu (cerbB-2) by manual examination of the digital slide of formalin-fixed, paraffin-embedded normal and neoplastic tissue immunohistochemically stained for HER-2 receptors on a computer monitor. When used with the Dako HercepTest™, it is indicated for use as an aid in the assessment of breast cancer patients for whom HERCEPTIN® (Trastuzumab) treatment is being considered. Note: The actual correlation of the Dako HercepTest™ to Herceptin® clinical outcome has not been established.

The ScanScope ® System is an automated digital slide creation, management, viewing and analysis system. The ScanScope® System components consist of an automated digital microscope slide scanner, computer, color monitor, keyboard and digital pathology information management software. The system capabilities include digitizing microscope slides at high resolution, storing and managing the resulting digital slide images, retrieving and displaying digital slides, including support for remote access over wide-area networks, providing facilities for annotating digital slides and entering and cditing metadata associated with digital slides, and facilities for image analysis of digital slides. Image analysis capabilities include the ability to detect and quantify characteristics useful to Pathologists, such as detecting and quantifying certain proteins revealed by immunohistochemical stains applied to histology specimens. The remote digital slide viewing capabilities of the system support reading digital slides on a computer monitor, enabling Pathologists to make clinically relevant decisions analogous to those they make using a conventional microscope. Specifically, the system supports the pathologist in the detection and semi-quantitative measurement of HER-2/neu (cerbB-2) by manual examination of the digital slide of formalin-fixed, paraffin-embedded normal and neoplastic tissue immunohistochemically stained for HER-2 receptors on a computer monitor.

Here's an analysis of the acceptance criteria and the study proving the device meets them, based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

The document does not explicitly state pre-defined acceptance criteria (e.g., "The device must achieve X% agreement"). Instead, it focuses on demonstrating "substantial equivalence" through agreement percentages within and between pathologists and methods. The performance is presented as ranges and specific percentages.

2. Sample Size Used for the Test Set and Data Provenance

• Test Set Sample Size:
  • Clinical Comparison Study: 180 formalin-fixed, paraffin-embedded breast tissue specimens.
  • Precision/Reproducibility Study: 8 HER2 slides (with two slides per HER2 score 0, 1+, 2+, and 3+).
• Data Provenance:
  • Clinical Comparison Study: 80 specimens from a "first clinical site" and 100 specimens from a "second clinical site." The text does not specify the country of origin, but it implies a clinical setting within the US given the FDA submission. The study was prospective in the sense that the readings were done as part of the study, rather than re-analyzing existing interpretations. The specimens themselves might have been collected retrospectively from existing tissue banks.
  • Precision/Reproducibility Study: The 8 HER2 slides were "sampled from one of the clinical sites." Similar to the above, the country of origin is not explicitly stated but implied to be within the US.

3. Number of Experts Used to Establish the Ground Truth for the Test Set and Their Qualifications

• Clinical Comparison Study: Three (3) pathologists at each of the two clinical sites were used, totaling six pathologists for the study (3 per site). The qualifications are stated as "Pathologists," which implies they are medical doctors specialized in pathology. No specific experience level (e.g., 10 years) is given.
• Precision/Reproducibility Study (for initial slide sampling): The "rounded average score of the manual microscopy scores provided by the three pathologists" was used to sample the 8 slides.
• Precision/Reproducibility Study (Intra-Pathologist): One pathologist.
• Precision/Reproducibility Study (Inter-Pathologists): Three pathologists.

4. Adjudication Method for the Test Set

The primary clinical comparison study used a "blinded manual examination" by individual pathologists. The agreement percentages are reported between pathologists and between methods (manual microscopy vs. digital reading for the same pathologist). There is no explicit mention of an adjudication method (like 2+1 or 3+1) to establish a single, definitive ground truth for each case by consensus or a senior expert for the entire test set. Instead, the study design allows for comparing agreement rates.

For the precision studies, "outliers are defined as scores that are different from the median values of the scores provided by the pathologist over 5 runs" (Intra-Pathologist) or "scores that are different from the median values of the scores provided by the three pathologists in this study" (Inter-Pathologist). This is a method for identifying discrepancies, not necessarily for adjudicating a final ground truth for each case for the purpose of primary performance metrics.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done, and the Effect Size of How Much Human Readers Improve with AI vs. Without AI Assistance

• Was an MRMC study done? Yes, a form of MRMC study was performed in the "Comparison studies: a. Method comparison with predicate device." It involved multiple readers (pathologists) and multiple cases (180 specimens). It compared two reading methods: manual microscopy and manual digital slide reading.

• Effect Size of AI assistance: The device (ScanScope XT System) is described as an "automated digital slide creation, management, viewing and analysis system." However, the "IHC HER2 Manual Read of Digital Slides application" specifically tested in the clinical comparison is for manual examination of digital slides by a pathologist. The document explicitly states: "The IHC HER2 Manual Read of Digital Slides application is intended for use as an aid to the pathologist in the detection and semi-quantitative measurement of HER-2/neu ... by manual examination of the digital slide...".

  Therefore, this study does not measure the effect size of AI assistance on human readers. It rather evaluates the equivalence of reading digital slides on a monitor to reading physical slides under a microscope.

  While there is a mention of "Aperio's IHC HER2 image analysis algorithm" within the precision/reproducibility section, that part of the study was not for clinical comparison or human reader improvement, but to objectively quantify system variability separate from pathologist variability. The clinical comparison specifically focuses on the manual read function of the digital slides by pathologists.

6. If a Standalone (Algorithm Only Without Human-in-the-Loop Performance) Was Done

Yes, a standalone performance assessment was conducted for the device's analytical capabilities in terms of image analysis on HER2 scores. This specifically evaluated "Aperio's IHC HER2 image analysis algorithm" (not the manual reading by pathologists). The precision studies (Intra-System, Inter-Day/Intra-System, Inter-System) were done using this algorithm, with results showing 100% agreement for calculated HER2 scores and very low standard deviations/ranges for cellular percentages. This demonstrates the performance of the algorithm without human intervention for specific analytical tasks, separate from the clinical "manual read" study.

7. The Type of Ground Truth Used

• Clinical Comparison Study (for the comparison itself): The ground truth for the comparison was essentially established by the pathologists' manual microscopic examination of the glass slides. The digital readings were compared against this traditional method, which serves as the established clinical standard. There isn't an "absolute" or "independent" ground truth like pathology reports from excisional biopsies or patient outcomes explicitly stated for each case in the comparison data. The predicate device for substantial equivalence also relies on manual microscopic assessment.
• Precision/Reproducibility Study (for sampling): The 8 slides used for precision studies were sampled based on the "rounded average score of the manual microscopy scores provided by the three pathologists," implying a consensus-based approach derived from expert readings.

8. The Sample Size for the Training Set

The document does not explicitly state a sample size for a "training set." The clinical study described is a comparison study and precision study, not a study for training or validating an AI model for clinical decision-making with direct human-in-the-loop assistance. While the text mentions "Aperio's IHC HER2 image analysis algorithm," it doesn't provide details on how this algorithm was trained or validated.

9. How the Ground Truth for the Training Set Was Established

Since no specific training set and its ground truth establishment are detailed for an AI model for clinical use in this submission, this information is not available in the provided text. The "ground truth" referenced for the analytical precision studies of the algorithm is inherent in its design to quantify cell features and use a scoring scheme mimicking pathologists' manual approaches.

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